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The role of ARID1A in endometriosis-related infertility

ARID1A 在子宫内膜异位症相关不孕症中的作用

基本信息

批准号：
9907119
负责人：
Ryan Marquardt
金额：
$ 3.6万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-16 至 2023-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907119
关键词：
Address Affect Characteristics Chromatin Remodeling Factor Complex Decidual Cell Reactions Defect Development Diagnosis Disease Early Diagnosis Emotional Endometrial Endometrium Environment Epithelial Epithelium Estrogens Fertility Functional disorder Genes Genetic Transcription Infertility Knockout Mice LIF gene Lesion Link Medical Medical Care Costs Molecular Morphology Mus Nucleosomes Ovarian Pain Pathway interactions Pregnancy Maintenance Progesterone Progesterone Receptors Proteins Regulation Research Resistance Role STAT3 gene Sampling Signal Pathway Signal Transduction Specificity System Testing Tissue Sample Tissues United States Uterine cavity Uterus Woman aged base child bearing early detection biomarkers early pregnancy loss endometriosis endometriosis-related infertility eutopic endometrium experience hormonal signals implantation improved outcome innovation mouse model natural Blastocyst Implantation protein complex reproductive steroid hormone tool uterine receptivity

项目摘要

ABSTRACT Endometriosis occurs when endometrial tissue grows outside the uterine cavity, and this painful disease afflicts about 10% of reproductive-aged women. Up to 50% of these women also experience infertility, and many cases cannot be explained by morphological or ovarian defects, which implicates a uterine environment non- receptive to embryo implantation. The molecular basis for the correlation of endometriosis and uterine non- receptivity is unclear, but it likely involves signaling downstream of the steroid hormones progesterone and estrogen in the endometrium. Progesterone and estrogen signaling must be tightly regulated for the successful establishment and maintenance of pregnancy but they imbalanced in endometriosis, leading to progesterone resistance and estrogen dominance. ARID1A, a chromatin remodeling factor, is directly associated with progesterone signaling through the progesterone receptor and is remarkably reduced in the endometrium of infertile women with endometriosis. ARID1A is necessary for fertility in mice due to its role supporting implantation, decidualization, and endometrial receptivity. Uterine loss of ARID1A results in aberrant epithelial proliferation characteristic of progesterone resistance in women with endometriosis. We hypothesize that ARID1A loss provides the molecular key to endometriosis-related infertility by causing increased endometriotic lesion development and decreased endometrial receptivity based on its role regulating steroid hormone signaling. We will address the complex problem of endometriosis-related infertility by examining the causal link between ARID1A loss in endometriotic lesions and the development of endometriosis-related infertility (Aim 1) as well as the endometrial compartment-specific role of ARID1A loss in the dysregulation of steroid hormone signaling observed in the eutopic endometrium of women endometriosis (Aim 2). Our innovative endometriosis model mice, uterine Arid1a knockout mice, and tissue samples from infertile women with endometriosis will be powerful tools to analyze ARID1A's role in the pathophysiology of endometriosis-related infertility and the dysregulated molecular mechanisms of steroid hormone signaling in the endometriosis-affected uterus.

抽象的当子宫内膜组织生长在子宫腔外时，就会发生子宫内膜异位症，这种痛苦的疾病折磨着人们。大约10%的育龄妇女。这些女性中高达 50% 还患有不孕症，而且许多女性都患有不孕症。病例不能用形态学或卵巢缺陷来解释，这意味着子宫环境非容易接受胚胎着床。子宫内膜异位症与子宫非正常相关性的分子基础接受性尚不清楚，但它可能涉及类固醇激素黄体酮的下游信号传导子宫内膜中的雌激素。黄体酮和雌激素信号必须受到严格调控才能成功建立和维持妊娠，但在子宫内膜异位症中它们不平衡，导致孕激素抵抗力和雌激素优势。 ARID1A 是一种染色质重塑因子，与孕酮信号通过孕酮受体传递，并且在子宫内膜中显着减少患有子宫内膜异位症的不孕妇女。 ARID1A 对于小鼠的生育能力是必需的，因为它具有支持性作用着床、蜕膜化和子宫内膜容受性。 ARID1A 子宫缺失导致异常上皮细胞子宫内膜异位症女性孕酮抵抗的增殖特征。我们假设 ARID1A 缺失通过导致子宫内膜异位症增加，为子宫内膜异位症相关不孕症提供了分子关键。基于类固醇激素调节作用的病变发展和子宫内膜容受性下降发信号。我们将通过检查因果关系来解决子宫内膜异位症相关不孕症的复杂问题子宫内膜异位病变中 ARID1A 缺失与子宫内膜异位相关不孕症发生之间的关系（目标 1）以及 ARID1A 缺失在类固醇激素失调中的子宫内膜室特异性作用在女性子宫内膜异位症的在位子宫内膜中观察到的信号传导（目标 2）。我们的创新子宫内膜异位症模型小鼠、子宫 Arid1a 基因敲除小鼠以及患有子宫内膜异位症的不孕妇女的组织样本将被分析 ARID1A 在子宫内膜异位症相关不孕症病理生理学中的作用的强大工具子宫内膜异位症影响的子宫中类固醇激素信号传导失调的分子机制。